Cleft palate (CP) is a common human malformation for which the etiology and pathogenesis remain largely unknown mainly because the cellular mechanisms mediating normal developmental processes in the palate are incompletely understood. Secalonic acid D (SAD) is among an increasing number of environmental chemicals and stresses capable of inducing CP in the offspring of exposed experimental rodents. Simultaneous exposure to dimethyl sulfoxide (DMSO) almost completely abolished the incidence of SAD-induced CP. Further evidence indicates that both the teratogenicity of SAD and DMSO-induced protection may involve SAD-induced increase in maternal glucocorticoid level and it's normalization by DMSO, respectively. Recent evidence indicates that the pathogenesis of CP induced by exogenous glucocorticoids, SAD and other cleft palate teratogens may involve alterations in the normal ontogeny of certain growth factors and oncogenes in the developing palate. These molecules along with protein kinases are known to play critical roles in the signalling pathways involved in cellular proliferation, differentiation, and other key events in normal embryonic, and thus palatal, development. The main objective of the study is to gain insight into the mechanisms of pathogenesis of cleft palate in mice by Secalonic acid D (SAD). It is expected that the SAD-related pathogenesis is relevant to cleft palatogenesis by other environmental causes. The Principal Investigator attempts to achieve this objective by addressing 3 specific aims and 7 hypotheses. The first aim focuses on the notion that the normal developing murine secondary palate exhibits a spatial and temporal pattern of distribution of epidermal growth factor (EGF), and oncogenes (myc and ras), and contains significant activity of protein kinases (A and C). The second specific aim focuses on the idea that the cleft palate teratogen SAD alters the ontogeny of one or more of these signalling molecules in the palate. The third specific aim addresses the idea that the protective agent DMSO reverses SAD-induced decrease in protein kinase A and increase in c-myc but not the other parameters proposed. The results of these studies will allow for identification of SAD-induced alterations in these very important signalling mechanisms, and for narrowing the focus to the most relevant changes by simultaneously identifying pathways(s) normalized (reversed) by the protective agent, DMSO. Further, these results are also likely to be relevant to the pathogenesis of CP by a large number of environmental chemicals, drugs and stresses that also seem to elevate maternal glucocorticoids. Identification of the mechanisms of pathogenesis of CP is critical in devising preventive strategies to deal with this common human malformation.